Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing

Abstract

TAL (transaldolase) was originally described in the yeast as an enzyme of the PPP (pentose phosphate pathway). However, certain organisms and mammalian tissues lack TAL, and the overall reason for its existence is unclear. Recently, deletion of Ser(171) (TALDeltaS171) was found in five patients causing inactivation, proteasome-mediated degradation and complete deficiency of TAL. In the present study, microarray and follow-up Western-blot, enzyme-activity and metabolic studies of TALDeltaS171 TD (TAL-deficient) lymphoblasts revealed co-ordinated changes in the expression of genes involved in the PPP, mitochondrial biogenesis, oxidative stress, and Ca(2+) fluxing. Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP. Nucleotide analysis showed depletion of NADPH and NAD(+) and accumulation of ADP-ribose. TD cells have diminished Deltapsi(m) (mitochondrial transmembrane potential) and increased mitochondrial mass associated with increased production of nitric oxide and ATP. TAL deficiency resulted in enhanced spontaneous and H(2)O(2)-induced apoptosis. TD lymphoblasts showed increased expression of CD38, which hydrolyses NAD(+) into ADP-ribose, a trigger of Ca(2+) release from the endoplasmic reticulum that, in turn, facilitated CD20-induced apoptosis. By contrast, TD cells were resistant to CD95/Fas-induced apoptosis, owing to a dependence of caspase activity on redox-sensitive cysteine residues. Normalization of TAL activity by adeno-associated-virus-mediated gene transfer reversed the elevated CD38 expression, ATP and Ca(2+) levels, suppressed H(2)O(2)- and CD20-induced apoptosis and enhanced Fas-induced cell death. The present study identified the TAL deficiency as a modulator of mitochondrial homoeostasis, Ca(2+) fluxing and apoptosis.

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

“…The GSH synthetase and transaldolase are enzymes involved in the generation of GSH 32 and NADPH, respectively. 41 The downmodulation of these two proteins in cells expressing the DN-STAT5A mutant could be responsible for their sensitivity to apoptosis via the decrease of their protective effect against oxygen-free radicals. The promoter of the GSH synthetase gene contains multiple binding sites for STAT family members including STAT5, suggesting that STAT5 might regulate the transcriptional activation of this gene.…”

GABP Transcription Factor (Nuclear Respiratory Factor 2) Is Required for Mitochondrial Biogenesis

“…Furthermore, Gabpa disruption caused very early embryonic lethality (39), which suggests that embryonic loss was not caused solely by its role in mitochondrial regulation. Gabpa disruption dramatically reduced Tfb1m expression, and the phenotype of reduced mitochondrial biogenesis was similar to that caused by short hairpin RNA knockdown of TFB1M.…”

The Neuroprotective Functions of Selenoprotein M and its Role in Cytosolic Calcium Regulation

“…1C-1D). DHR123 is used as a fluorescent indicator for reactive oxygen species (ROS) generation measured such that increases in ROS production increase fluorescence (20,33). Cells overexpressing SelM showed significantly reduced ROS production when measured by DHR123 fluorescence in the presence of varying concentrations of hydrogen peroxide (Figs.…”